Cytomegalovirus (CMV) is a ubiquitous pathogen infecting most humans. Like other herpes viruses, these infections are controlled but not completely eradicated. Dormant virus remaining in multiple tissues can reactivate during times of stress or immune compromise. We and numerous others have recognized that CMV reactivation occurs in lungs of ~33% of immune competent patients during critical illness. CMV is an accepted pathogen in immune suppressed patients that is increasingly being recognized as a potential pathogen in critically ill immune competent patients. Recent clinical data have associated CMV reactivation with worsened morbidity and mortality in these patients, prompting a prospective clinical trial with antiviral treatment (1U01HL102547). It is our overarching hypothesis that latent CMV infection and the immune responses to it have pathogenic potential for this patient population. Because of limitations in human studies, we have developed a murine model of CMV latency/reactivation. Using this model, we have confirmed that CMV reactivation triggered by sepsis can cause lung injury in immunocompetent hosts, a finding that supports available clinical data. Despite these significant advances, three major gaps remain in our understanding: 1) How does CMV predispose immune competent hosts to lung injury, 2) Can we identify those most at risk for CMV related injury, and 3) Can CMV-related risk be ameliorated in immune competent hosts? In this proposal we will address each of these specific questions using our animal model. In Aim 1 we will study mechanisms of lung injury during CMV reactivation in immunocompetent hosts. We will test the hypothesis that CMV infection preconditions the host to develop an immunopathologic immune potential that is unleashed by bacterial sepsis. In Aim 2 we will study a new application of available methods to determine risk for reactivation and poor outcome. We will test the novel hypothesis that CMV IgG titers will predict viral load and CMV-related risk. In Aim 3 we will test two highly novel approaches to prevent CMV reactivation. We will test the hypothesis that CMV-related risk can be mitigated in previously infected hosts. These studies represent a direct continuation of our previous work, and we expect that knowledge gained from this proposal will continue to translate directly into diagnostic and therapeutic strategies that will improve care for critically ill patients. PUBLIC HEALTH RELEVANCE: CMV infects ~50-60% of Americans by school age and up 80-90% by retirement. CMV is not cleared, but becomes dormant after primary infection, periodically reactivating during times of stress or immune compromise. CMV reactivation is a difficult complication in transplant patients that until recently has received little attention in immune competent patients. We (and others) have recently observed that many previously healthy patients with latent CMV experience unrecognized reactivation of this virus during critically illness or injury. This is associated with lung disease and prolonged ventilator durations. Previously healthy patients with CMV reactivation also have roughly double the risk of dying (55% versus 30%) in the hospital than patients without reactivation. Millions of patients are hospitalized each year in intensive care units throughout the country, and ~ 1 in 3 at risk will reactivate this virus during their illness.